Akdim Fatima, Stroes Erik S G, Kastelein John J P
Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands.
Curr Opin Lipidol. 2007 Aug;18(4):397-400. doi: 10.1097/MOL.0b013e328248b4ad.
Antisense oligonucleotides are novel therapeutic agents that reduce the number of specific mRNAs available for translation of the encoded protein. ISIS 301012 is an antisense oligonucleotide developed to reduce the hepatic synthesis of apolipoprotein B-100. Apolipoprotein B-100 is made in the liver, and antisense oligonucleotides preferentially distribute to that organ, so antisense apolipoprotein B-100 may have potential as an efficacious lipid-lowering agent.
Recently, in healthy volunteers and in mild dyslipidaemic patients, this strategy as monotherapy or in conjunction with statins has shown unparalleled efficacy in reducing apolipoprotein B-100 and LDL-cholesterol. Tolerance for this novel therapy is encouraging and safety concerns currently only relate to mild injection-site reactions and rare liver-function test abnormalities. It should be noted, however, that these safety results were obtained in relatively few individuals.
ISIS 301012 has initially shown promising results in experimental animal models, and in clinical trials in humans. Besides the effect of reducing apolipoprotein B-100 and LDL-cholesterol, this compound also significantly lowers plasma triglycerides. Safety concerns related to the drug include increased liver-function tests. To date no evidence of hepatic steatosis has been reported. Nonetheless, clinical trials of longer duration are required to demonstrate further safety.
反义寡核苷酸是新型治疗药物，可减少可用于翻译编码蛋白的特定mRNA数量。ISIS 301012是一种开发用于减少载脂蛋白B-100肝脏合成的反义寡核苷酸。载脂蛋白B-100在肝脏中产生，且反义寡核苷酸优先分布至该器官，因此反义载脂蛋白B-100可能具有作为有效降脂药物的潜力。
最近，在健康志愿者和轻度血脂异常患者中，这种策略作为单一疗法或与他汀类药物联合使用，在降低载脂蛋白B-100和低密度脂蛋白胆固醇方面显示出无与伦比的疗效。对这种新型疗法的耐受性令人鼓舞，目前的安全问题仅涉及轻度注射部位反应和罕见的肝功能检查异常。然而，应该注意的是，这些安全结果是在相对较少的个体中获得的。
ISIS 301012最初在实验动物模型和人体临床试验中均显示出有前景的结果。除了降低载脂蛋白B-100和低密度脂蛋白胆固醇的作用外，该化合物还能显著降低血浆甘油三酯。与该药物相关的安全问题包括肝功能检查结果升高。迄今为止，尚未报告肝脂肪变性的证据。尽管如此，仍需要进行更长时间的临床试验以进一步证明安全性。
